Design, Synthesis, and Pharmacological Characterization of (+)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY354740):  A Potent, Selective, and Orally Active Group 2 Metabotropic Glutamate Receptor Agonist Possessing Anticonvulsant and Anxiolytic Properties

Abstract

2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (9) was designed as a conformationally constrained analog of glutamic acid. For 9, the key torsion angles (tau 1 and tau 2) which determine the relative positions of the alpha-amino acid and distal carboxyl functionalities are constrained where tau 1 = 166.9 degrees or 202 degrees and tau 2 = 156 degrees, respectively. We hypothesized that 9 would closely approximate the proposed bioactive conformation of glutamate when acting at group 2 metabotropic glutamate receptors (mGluRs). The racemic target molecule (+/-)-9, its C2-diastereomer (+/-)-16, and its enantiomers (+)-9 (LY354740) and (-)-9 (LY366563) were prepared by an efficient, stereocontrolled, and high-yielding synthesis from 2-cyclopentenone. Our hypothesis that 9 could interact with high affinity and specificity at group 2 mGluRs has been supported by the observation that (+/-)-9 (EC50 = 0.086 +/- 0.025 microM) and its enantiomer (+)-9 (EC50 = 0.055 +/- 0.017 microM) are highly potent agonists for group 2 mGluRs in the rat cerebral cortical slice preparation (suppression of forskolin-stimulated cAMP formation) possessing no activity at other glutamate receptor sites (iGluR or group 1 mGluR) at concentrations up to 100 microM. Importantly, the mGluR agonist effects of (+)-9 are evident following oral administration in mice in both the elevated plus maze model of anxiety (ED50 = 0.5 mg/kg) and in the ACPD-induced limbic seizure model (ED50 = 45.6 mg/kg). Thus, (+)-9 is the first orally active group 2 mGluR agonist described thus far and is an important tool for studying the effects of compounds of this class in humans.

Anxiolytic Activity of the MGLU2/3 Receptor Agonist LY354740 on the Elevated Plus Maze is Associated with the Suppression of Stress-Induced c-Fos in the Hippocampus and Increases in c-Fos Induction in Several Other Stress-Sensitive Brain Regions

“…Effect of LY354740 (20 mg/kg, s.c.) on EPM Behavior LY354740 (20 mg/kg, s.c.) administered 30 min prior to the EPM test significantly increased anxiolytic-like behavior in the outbred ICR:CD-1 strain of mice, which is consistent with previous reports using other mouse strains (Monn et al, 1997;Helton et al, 1998). LY354740-treated mice spent significantly more time in the open arms and entered the open arms more frequently than saline-treated mice ( Figure 2a and b).…”

“…(1S,2S,5R,6S)-2-aminobicyclo [3.1.0]hexane-2,6-dicarboxylic acid (LY354740) is a selective and potent agonist for mGlu2 and mGlu3 receptors (Monn et al, 1997). It activates human cloned mGlu2 and mGlu3 receptors in non-neuronal cells with EC 50 values of 5 and 24 nM, respectively, while EC 50 values for other mGlu receptors were 36 mM (mGlu8) or higher (EC 50 4100 mM for mGlu1, 5, 4, 7) (reviewed by Schoepp et al, 1999b).…”

“…It activates human cloned mGlu2 and mGlu3 receptors in non-neuronal cells with EC 50 values of 5 and 24 nM, respectively, while EC 50 values for other mGlu receptors were 36 mM (mGlu8) or higher (EC 50 4100 mM for mGlu1, 5, 4, 7) (reviewed by Schoepp et al, 1999b). LY354740 produces anxiolytic-like effects in several animal models of anxiety, including fear-potentiated startle (Helton et al, 1998), elevated plus maze (EPM) (Monn et al, 1997;Helton et al, 1998;Ferris et al, 2001), conflict drinking test (Klodzinska et al, 1999), and stress-induced hyperthermia (Spooren et al, 2002). LY354740 is also active in an animal model of panic disorder (Shekhar and Keim, 2000).…”

Efficacy and Tolerability of an mGlu2/3 Agonist in the Treatment of Generalized Anxiety Disorder

“…LY354740 has evidenced activity in a number of rodent stress and anxiety models, including fear-potentiated startle, elevated plus maze, lactate-induced panic, and stress-induced hyperthermia (Walker et al, 2002;Tizzano et al, 2002;Monn et al, 1997;Shekhar and Keim, 2000;Spooren et al, 2002). Importantly, the effects of LY354740 occur at doses that are not associated with psychomotor impairment, which is common with benzodiazepine pharmacology (Helton et al, 1998;Tizzano et al, 2002).…”

The Effect of Intrahippocampal Injection of Group II and III Metobotropic Glutamate Receptor Agonists on Anxiety; the Role of Neuropeptide Y

“…Behavioral studies conducted by many authors have shown that the increase in glutamatergic activity leads to anxiety; conversely, inhibition of this transmission produces antianxiety effects Pilc et al, 2000;Tatarczynska et al, 2001;Helton et al, 1998;Monn et al, 1997;Dunn et al, 1989). L-SOP and L-CCG-I are agonists of group III mGluRs and it is generally accepted that the activation of these receptors results, via a presynaptic mechanisms, in a modulatory inhibition of Glu transmission (Gereau and Conn, 1995;Vignes et al, 1995).…”